High levels of VEGF have been observed in the serum of MM patients and elevated pleural effusion VEGF levels are associated with poor survival in patients with MM. VEGF may also act in a functional autocrine loop capable of directly stimulating the growth of MM cells. MM cell lines express elevated levels of both VEGF and the VEGFR-1 and 2 compared with normal mesothelial cells. VEGF activated these receptors and increased proliferation of all MM cell lines examined. Interestingly, significant vascularization is rarely exhibited in MM suggesting that VEGF may play a key role in MM tumor progression by primarily regulating tumor cell proliferation suggesting VEGF/VEGFR as therapeutic targets in MM. The rate-limiting step of the mevalonate pathway is the conversion of HMG-CoA to mevalonate, which is catalyzed by HMG-CoA reductase. The mevalonate pathway produces various end products that are critical for many different cellular functions including cholesterol, dolichol, ubiquinone, Tubacin isopentenyladenine, geranylgeranyl pyrophosphate, and farnesyl pyrophosphate. Geranylgeranyl 
transferase and farnesyl transferase use GGPP and FPP, respectively, for post-translational modifications of a wide variety of cellular proteins including the Ras, Rab, and Rho families. These proteins regulate cell proliferation, intracellular trafficking and cell motility and this post-translational modification functions as a high throughput screening membrane anchor critical for their activity. Blockade of the rate-limiting step of the mevalonate pathway by HMG-CoA reductase inhibitors results in decreased levels of mevalonate and its downstream products and, thus, may have significant influences on many critical cellular functions. Malignant cells appear highly dependent on the sustained availability of the end products of the mevalonate pathway. The statin family of drugs are potent inhibitors of HMG-CoA reductase that are widely used as hypercholesterolemia treatments. Mevalonate metabolites are required for the proper function and localization of a number of downstream mediators of the VEGFR-2 signaling cascade. Proteins that require FPP or GGPP posttranslational modifications play critical roles in transducing these signals. In our recent studies, we have demonstrated that lovastatin treatment inhibits ligandinduced activation of EGFR. The mechanism by which EGFR inhibition is mediated by lovastatin is novel and suggests a previously unrecognized process controlling EGFR activity. Due to the potential of lovastatin to target EGFR function and its downstream signaling, we previously evaluated the effects of combining lovastatin with the clinically relevant EGFR tyrosine kinase inhibitor gefitinib. The combination of gefitinib and lovastatin demonstrated significant co-operative cytotoxic effects when cells were pretreated with lovastatin for 24 hrs. At this time point, lovastatin demonstrated significant inhibition of EGFR function. We demonstrated co-operative cytotoxic effects with this combination that was synergistic due to the induction of a potent apoptotic response. In this study, we evaluated the potential of lovastatin to similarly inhibit VEGFR-2 function. Furthermore, we evaluated the effects of lovastatin on endothelial cell proliferation and survival as well as the effects of combining lovastatin with VEGFR-TKIs on MM tumor cell viability as a potential novel therapeutic approach. In our previous study, we demonstrated that the targeting of HMG-CoA reductase, which results in mevalonate depletion, can inhibit the function of the EGFR.